Summary of Clinical Data

Authors

Ennis WJ, Foremann P, Mozen N, Massey J, Conner-Kerr T, Meneses P

Study design

Multicenter, double-blind, sham-controlled randomized trial (26 sites)

Patients

55 completed the treatment course (27 MIST, 28 sham)

Wound type

Recalcitrant diabetic foot ulcers

Treatment

3 times per week for 12 weeks

Results

• Wound closure at 12 weeks: 40.7% vs 14.3% sham, p=0.0366
• No difference in the number and type of adverse events between groups

Conclusion: Compared to control, this therapeutic modality was found to increase the healing rate of recalcitrant diabetic foot ulcers.

Authors

Yao M, Hasturk H, Kantarci A, Gu G, Garcia-Lavin S, Fabbi M, Park N, Hayashi H, Attala K, French MA, Driver VR

Study design

Randomized pilot, 3 arms (MIST 3 times per week, MIST once per week, standard care)

Patients

12 (4 per arm)

Wound type

Nonhealing diabetic foot ulcers

Treatment

4 weeks

Results

• Wound area reduction: 86% (MIST 3 times per week) vs 25% (MIST once per week) vs 39% (standard care), p<0.05

Conclusion: This proof-of-concept pilot study demonstrates that NCLF-US is effective in treating neuropathic diabetic foot ulcers through, at least in part, inhibiting pro-inflammatory cytokines in chronic wound and improving tissue regeneration. Biochemical and histological analyses indicated a trend towards reduction of pro-inflammatory cytokines (IL-6, IL-8, IL-1β, TNF-α and GM-CSF), matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) and macrophages in response to NCLF-US consistent with wound reduction.

Authors

Gibbons GW, Orgill DP, Serena TE, Novoung A, O'Connell JB, Li WW, Driver VR

Study design

Multicenter randomized controlled trial (22 sites) with 2-week standard-care run-in

Patients

81 randomized (41 MIST plus standard care, 40 standard care)

Wound type

Venous leg ulcers

Treatment

3 times per week for 4 weeks

Results

• Wound area reduction at 4 weeks: 61.6% vs 45.0%, p=0.02
• Pain (VAS) reduction at 4 weeks: 80% vs 20%, p=0.01
• Complete closure at 7 weeks: 28% vs 15%

Conclusion: NLFU therapy with guideline-defined standard VLU care should be considered for healing VLUs not responding to standard care alone.

Authors

Olyaie M, Rad FS, Elahifar MA, Garkaz A, Mahsa G

Study design

Randomized controlled trial, 3 arms (MIST, high-frequency ultrasound, standard care)

Patients

90 (30 per arm)

Wound type

Venous leg ulcers

Treatment

3 times per week for 3 months or until healed

Results

• Mean time to complete healing: 6.65 months (MIST) vs 8.50 months (standard care), p=0.001
• Wound area reduction at 4 months: 72.8% (MIST, 10.01 to 2.72 cm²) vs 55.4% (standard care, 9.60 to 4.28 cm²), p=0.02
• Pain score (0 to 20 scale) at 4 months: 3.26 (MIST) vs 5.10 (standard care), p=0.02

Conclusion: Outcomes of both methods of ultrasound therapy were better than standard care alone, and some differences between the two ultrasound therapy groups were observed, but they were not statistically significant.

Authors

Beheshti A, Shafigh Y, Parsa H, Zangivand AA

Study design

Randomized controlled trial, 3 arms (MIST, high-frequency ultrasound, standard care)

Patients

90 (30 per arm)

Wound type

Venous leg ulcers

Treatment

3 times per week until healed

Results

• Mean time to complete healing: 5.70 months (MIST) vs 8.13 months (standard care), p<0.0001
• Mean wound size at 4 months: 3.30 cm² (MIST, from 9.10) vs 4.80 cm² (standard care, from 8.96), p=0.01
• Pain score (0 to 20 scale) at 4 months: 4.20 (MIST, from 9.43) vs 6.56 (standard care, from 9.90), p<0.0001

Conclusion: Our results in the present study show the significant effectiveness of ultrasound therapy in wound healing. Differences between the two ultrasound therapy groups were not statistically significant.

Authors

Kavros SJ, Miller JL, Hanna SW

Study design

Randomized controlled trial, single site

Patients

70 (35 MIST plus standard care, 35 standard care)

Wound type

Nonhealing leg and foot ulcers with chronic critical limb ischemia

Treatment

3 times per week, 5 minutes per treatment, for 12 weeks or until fully healed

Results

• Patients achieving >50% reduction in wound size at 12 weeks: 63% vs 29%, p<0.001

Conclusion: The rate of healing of cutaneous foot and leg ulcerations in patients with chronic critical limb ischemia improved significantly when MIST Therapy was combined with the standard of wound care.

Authors

Prather JL, Tummel EK, Patel AB, Smith DJ, Gould LJ

Study design

Randomized controlled trial with blinded outcome adjudication

Patients

33 enrolled, 27 randomized

Wound type

Split-thickness skin graft donor sites

Treatment

Daily for 5 days

Results

• Time to first "no drainage": 12.1 vs 21.3 days, p=0.04
• Time to 2 consecutive visits with no drainage: 16.1 vs 28.1 days, p=0.02
• Time to adjudicated full epithelialization: 18.2 vs 27.5 days, p=0.03
• Recidivism at 6 weeks: 8% vs 45%, p=0.06
• All MIST subjects had epithelialized by 4 weeks compared with 71% of standard care
• Pain scores were reduced and significant differences in itching were observed

Conclusion: Noncontact low-frequency ultrasound and standard care compared with standard care alone demonstrated significant accelerated healing and reduced pain and itching. Noncontact low-frequency ultrasound subjects experienced a better quality of healing with less incidence of infection and recidivism.

Authors

Voigt J, Wendelken M, Driver V, Alvarez OM

Study design

Systematic review and meta-analysis of 8 randomized controlled trials of low-frequency ultrasound

Patients

77 in the pooled noncontact analysis (2 sham-controlled trials)

Wound type

Chronic lower-limb wounds (venous and diabetic foot ulcers)

Results

• Noncontact low-frequency ultrasound reduced the proportion of non-healed wounds at 3 months: relative risk 0.74 (95% CI 0.58 to 0.95), p=0.02

Conclusion: In patients presenting with either venous stasis or diabetic foot ulcers (Wagner classification 1-3), early healing appears to be facilitated by either low-frequency low-intensity noncontact ultrasound or low-frequency high-intensity contact ultrasound.

Authors

Escandon J, Vivas AC, Perez R, Kirsner R, Davis S

Study design

Open-label prospective pilot

Patients

10 ulcers

Wound type

Large refractory venous leg ulcers

Treatment

3 times per week for 4 weeks, with compression

Results

• Significant reduction in wound area over 4 weeks, p=0.0039

Conclusion: Patients treated with ultrasound therapy and compression therapy show clinical improvement over the course of 4 weeks and had a decrease in inflammatory cytokines, bacterial counts and pain.

Authors

Honaker JS, Forston MR, Davis EA, Weisner MM, Morgan JA, Sacca E

Study design

Prospective study with historical case-control comparison

Patients

60 (30 MIST plus standard care, 30 standard care)

Wound type

Deep tissue pressure injury, treated within 5 days of onset

Results

• Change in total surface area: -8.8 cm² vs -0.3 cm², p=0.014
• Severity score at discharge (Honaker scale, 3 to 18): 7.6 vs 11.9, p=0.0001
• Final stage: MIST group mostly Stage 2 (50%) or DTPI (23%); control group mostly unstageable (57%) or DTPI (27%)

Conclusion: Deep tissue pressure injury treated with noncontact low frequency ultrasound within 5 days of onset and in conjunction with standard of care may improve outcomes as compared to standard of care only.

Authors

Honaker JS, Forston MR, Davis EA, Wiesner MM, Morgan JA

Study design

Retrospective case-control analysis

Patients

85 patients, 127 suspected deep tissue injuries (63 MIST, 64 control)

Wound type

Suspected deep tissue injury (pressure)

Results

• Resolution: 18% vs 2%
• Significant reduction in injury severity score vs control (p<0.00)

Authors

Wagner-Cox P, Duhame HM, Jamison CR, Jackson RR, Fehr ST

Study design

Retrospective analysis, single site

Patients

44 (22 hospital-acquired, 22 present on admission)

Wound type

Deep tissue pressure injury

Treatment

Daily for 5 days, then 3 times per week

Results

• Mean injury size: 24.6 cm² to 14.4 cm², p=0.02
• Resolved at completion of treatment: 23%

Conclusion: Study findings suggest that NLFU is a viable and promising treatment option for both HADTPI and DTPI POA.

Authors

Serena T, Lee SK, Lam K, Attar P, Meneses P, Ennis W

Study design

Prospective clinical study (3 sites) with supporting in vitro and animal experiments

Patients

11 evaluable (18 enrolled)

Wound type

Stage III pressure ulcers with bacterial load above 100,000 CFU/g

Treatment

3 times per week for 2 weeks

Results

• Mean bacterial load reduced from 4 x 10⁷ to 2 x 10⁷ CFU/g
• Wound area reduced 26% (13.8 to 10.8 cm²)
• No wounds showed signs of clinical infection during treatment and no adverse events were observed

Conclusion: Taken together, these four studies indicate that noncontact ultrasound can be used to reduce bacterial quantity.

Authors

Ennis WJ, Valdes W, Gainer M, Meneses P

Study design

Prospective study with historical controls

Patients

23 patients, 29 wounds

Wound type

Chronic wounds of mixed etiology (diabetic, venous, ischemic, pressure, postoperative, inflammatory)

Results

• Wounds healed: 69% (31% with MIST alone; 38% with MIST plus adjunct therapy added after a healing plateau)
• Mean healing time 8 weeks (median 7 weeks) vs median 10 weeks for historical controls
• Historical control healing rate: 72%

Authors

Viana L, Pompeo MQ

Study design

Prospective pilot study (registered NCT02045303)

Patients

11 patients, 24 wounds enrolled; 6 patients, 12 wounds completed

Wound type

Chronic and subacute lower-extremity wounds

Treatment

Contact ultrasound for debridement, then MIST 3 times per week; 12 weeks

Results

• Wounds 4 to 21 weeks old: 75% reached >99% closure by 12 weeks; all reached 100% granulation
• Wounds 47 weeks or older: 50% reduced in area; all improved in granulation

Conclusion: Both groups benefited from the VIP Protocol, which promoted wound closure or wound bed preparation for graft. The results seem to favor an earlier start of the protocol for best outcomes and indicate that contact and noncontact ultrasound therapies are not exclusionary but rather complementary.

Authors

Kavros SJ, Liedl DA, Boon AJ, Miller JL, Hobbs JA, Andrews KL

Study design

Retrospective comparative analysis; all wounds followed for 6 months

Patients

210 (163 MIST plus standard care, 47 standard care)

Wound type

Chronic lower-extremity wounds

Treatment

3 times per week for 90 days or until healed

Results

• Wounds healed: 53% vs 32%, p=0.009
• Rate of healing (regression slope of wound volume): 1.4 vs 0.22, p=0.002

Conclusion: The rate of healing and complete closure of chronic wounds in patients improved significantly when MIST Therapy was combined with standard wound care.

Authors

Kavros SJ, Schenck EC

Study design

Retrospective analysis; each patient's prior standard-care period served as comparison

Patients

51

Wound type

Chronic lower-leg and foot ulcers

Treatment

Standard care for a mean of 9.8 ± 5.5 weeks, followed by MIST for a mean of 5.5 ± 2.8 weeks

Results

• Wounds closed: 51% (26 of 51) during MIST treatment vs 0% during the prior standard-care period
• Time to healing: 5.5 ± 2.8 weeks (MIST) vs 9.8 ± 5.5 weeks (standard care), p<0.0001
• Wound volume reduction: 94.9% ± 9.8% (MIST) vs 37.3% ± 18.6% (standard care), p<0.0001

Authors

Cole PS, Quisberg J, Melin MM

Study design

Retrospective analysis

Patients

41 patients, 52 wounds

Wound type

Surgical, trauma, and chronic wounds

Treatment

3 to 16 weeks

Results

• Complete healing: 38% of wounds

Authors

Bell AL, Cavorsi J

Study design

Retrospective chart review

Patients

76

Wound type

Nonhealing wounds of mixed etiology

Treatment

Mean 4.3 weeks

Results

• Wounds with >75% granulation tissue: 32% before treatment to 46% after
• Wounds free of slough: 27% before treatment to 55% after

Authors

Gehling ML, Samies JH

Study design

Retrospective chart review

Patients

15

Wound type

Painful nonhealing lower-extremity wounds

Treatment

2 to 4 weeks

Results

• Mean pain score: 8.07 ± 1.91 before treatment to 1.67 ± 1.76 after, p=0.0003 (79% reduction)
• No patients reported worsening pain after treatment commenced

Authors

Driver VR, Yao M, Miller CJ

Study design

Meta-analysis of 8 published studies

Patients

444 MIST-treated patients

Wound type

Chronic wounds of mixed etiology

Results

• Wound area reduction: 85.2% (95% CI 64.7% to 97.6%) over a mean of 7 weeks (4 studies, N=188)
• Wound volume reduction: 79.7% (95% CI 46.1% to 98.8%) over a mean of 12 weeks (4 studies, N=278)
• Wounds healed: 32.7% by 6 weeks (95% CI 23.3% to 42.1%) and 41.7% by 12 weeks (7 studies, N=429)
• Mean time to healing 8.2 weeks (median 6.8 weeks)

Conclusion: NLFU for treatment of chronic wounds was associated with consistent and substantial wound size reductions, as well as favorable rates of healing.

Authors

Tricco AC, Antony J, Vafaei A, et al.

Study design

Overview of 99 systematic reviews of complex-wound interventions

Patients

Not applicable (overview of reviews)

Wound type

Venous, diabetic, pressure, mixed, and surgical wounds

Results

• Noncontact low-frequency ultrasound rated effective for diabetic foot ulcers, based on a high-quality meta-analysis (AMSTAR score ≥8; Voigt 2011)